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Maple syrup urine disease
A rare inherited disorder of branched-chain amino acid metabolism classically characterized by poor feeding, lethargy, vomiting and a maple syrup odor in the cerumen (and later in urine) noted soon after birth, followed by progressive encephalopathy and central respiratory failure if untreated. The four overlapping phenotypic subtypes are: classic, intermediate, intermittent and thiamine-responsive MSUD.
ORPHA:511Classification level: Disorder
- BCKD deficiency
- BCKDH deficiency
- Branched-chain 2-ketoacid dehydrogenase deficiency
- Branched-chain ketoaciduria
- Prevalence: 1-9 / 1 000 000
- Inheritance: Autosomal recessive
- Age of onset: Infancy, Neonatal, Childhood
- ICD-10: E71.0
- OMIM: 248600 615135
- UMLS: C0024776 C0268576
- MeSH: D008375
- GARD: 3228
- MedDRA: 10026817
The estimated prevalence is around 1/150,000 live births, from published and unpublished newborn screening data.
Classic MSUD presents in the first days of life with poor feeding and drowsiness followed by a worsening encephalopathy with lethargy, intermittent apnea, stereotypic movements ("fencing" and ''bicycling") and opisthotonus. Coma and central respiratory failure supervene 7 to 10 days after birth. The only abnormality in biochemistry is ketosis. Intermediate MSUD clinically resembles classic MSUD but it can have a later onset and less severe symptoms. Intermittent MSUD patients are asymptomatic at birth but may suffer episodes of acute decompensation or develop neurological symptoms and developmental delay during childhood. Thiamin-responsive MSUD is clinically similar to intermediate MSUD with thiamin therapy improving dietary leucine tolerance.
MSUD is due to mutations in the genes encoding subunits E1a, E1b, and E2 of the branched chain 2-ketoacid dehydrogenase (BCKAD) complex, involved in the second enzymatic step in the degradation of the branched chain amino acids (BCAAs): leucine, isoleucine and valine. BCKAD has four subunits: E1a, E1b, E2, and E3, which are encoded by the genes BCKDHA (19q13.1-q13.2), BCKDHB (6q14.1), DBT (1p31) and DLD (7q31-q32) respectively. Mutations in these genes lead to the accumulation of BCAAs (especially leucine) and their branched-chain alpha-ketoacids. Mutations in the E3 subunit gene (DLD) are not associated with MSUD but lead to pyruvate dehydrogenase E3 deficiency (see this term). A mutation in the PPM1K gene (4q22.1) has been reported in a single case of mild intermediate MSUD.
MSUD follows an autosomal recessive inheritance pattern and genetic counseling is possible.
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